It has not yet been found a satisfactory composition or method of treatment suppressing the growth of cancer (malignant tumor) reliably and hardly causing side effects, so development thereof is strongly desired.
In general, cancer cells repeat rapid proliferation, so uptake of essential amino acids, unable to be produced in intracellular metabolism, is abnormally increased. The present inventors have succeeded in molecular cloning of a cancer-specific L-type amino acid transporter which is a membrane protein required for cellular uptake of neutral branched chain amino acids and aromatic amino acids including a number of essential amino acids. The present inventers named this as a system L amino acid transporter 1 (LAT1) (Kanai Y. et al., Journal of Biological Chemistry, 273, 23629(1998)). After that, the present inventers have been searching for the agent composition selectively inhibiting LAT1 and LAT1 genes.
The types of cancer, for example, can be cited lung cancer, stomach cancer, pancreatic cancer, esophageal cancer, breast cancer, colon cancer, bladder cancer, prostate cancer and blood cancer, etc. In the following, blood cancer, stomach cancer, pancreatic cancer and colon cancer is described as an example.
As blood cancer (hematopoietic organ tumor), leukemia, lymphoma, myeloma, etc. are mentioned.
Leukemia is divided into 4 types (acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia: all, chronic lymphatic leukemia). Acute Leukemia is a disease in which tumor genesis occurs in the hematopoietic stem cells or hematopoietic progenitor and only specific cells grow as leukemia cells.
Lymphoma is a tumor derived from the cells constituting lymphatic tissues, and is hematopoietic cell tumors caused mainly by canceration of lymphocytes. Malignant lymphoma is divided into Hodgkin's disease and non-Hodgkin's lymphoma.
Lymphocytic leukemia and lymphoma which are canceration of major constituent cells of lymphocytes are divided into B lymphocytic tumors and T lymphocytic tumors. T lymphocytic tumors include acute T lymphocytic leukemia (T-ALL), T Lymphoblastic Lymphoma (T-LL), chronis T lymphocytic leukemia (T-CLL), adult T cell leukemia (ATL) and the like.
Lymphoblastic Lymphoma (LL) is canceration lymphocytes at more immature stages of differentiation compared to the general lymphoma, and the nature of the cancer cells thereof is considered to be the same as acute lymphocytic leukemia. Therefore, they are classified to a group of diseases as “Precursor T- or B-Lymphoblastic Leukemia/Lymphoma” In the WHO classification.
T-cell lymphoblastic lymphomas (T-LL) and T-cell acute lymphoblastic leukemia (T-ALL) are highly aggressive diseases which originate from the transformation of thymocytes blocked at different stages of differentiation (Non-Patent Literature 1). T-ALL represents approximately 15 and 30% of all adult and childhood non-Hodgkin lymphomas, respectively. In recent years, aggressive chemotherapy treatments in T-ALL patients have improved cure rates to greater than 40% in adult and 80% in pediatric patients (Non-Patent Literature 2); however, refractory relapses are well-known to occur in all available drug treatments (Non-Patent Literature 3). Consequently, the present inventors deem that more knowledge regarding the molecular mechanisms involved in the pathogenesis of T cell malignancies is absolutely vital in order to identify novel and/or combinational treatments to enhance these cure rates.
Tumorigenic cells (cancer cells) are well-known to display hallmark properties (Non-Patent Literature 4) which allow them to continuously proliferate, escape elimination by apoptosis, disseminate and resist treatments. Cancer cells have reprogrammed their metabolism (Non-Patent Literature 5); a property which has enhanced their ability to sequester nutrients required to produce new proteins, lipids and DNA in order for the cancer cells to quickly grow and actively divide. Because they harbor different genetic lesions, such as chromosomal translocations that promote oncogenic proliferation and perturb differentiation, T-ALL/T-LL cells are highly heterogeneous at the molecular level (Non-Patent Literature 1). Nevertheless, it has been shown that they have a common and essential activation of the Phosphatidylinositide 3-Kinase/Protein Kinase B; PKB (PI3K/Akt) pathway (Non-Patent Literature 6). PI3K/Akt is repressed by the tumor suppressor gene PTEN (phosphatase and tensin homolog deleted on chromosome 10) which is frequently inactivated in human cancers (Non-Patent Literature 7). The PTEN lipid phosphatase activity counteracts the action of PI3K-explicitly involved in cell survival (i.e. growth, proliferation, intracellular trafficking)—by reversing phosphatidylinositol (3,4,5)-triphosphate (PIP3) to phosphatidylinositol 4,5-bisphosphate (PIP2) which prevents Akt activation and downstream proliferative events. In the absence of PTEN, Akt is fully active and stimulates cells toward cancerous transformation (Non-Patent Literature 8, 9).
In order to investigate PTEN's participation at the molecular level in the pathogenesis of T-ALL/T-LL, the present inventors utilized a murine model exhibiting a conditional, T-cell specific, PTEN deletion (PTENf/f×lck-Cre) (Non-Patent Literature 10). The resulting progeny (tPTEN−/− mice) quickly develop aggressive and invasive T cell lymphomas and die within 6 to 20 weeks. In order to highlight the deregulated genes that support tPTEN−/− lymphomagenesis, a transcriptomic (expression profiling) analysis was performed which identified SLC7A5 gene up-regulation. SLC7A5 encodes System L Amino Acid Transporter 1 (LAT1). In recent years, significant findings have demonstrated that many cancerous and/or proliferating cells are strongly linked to LAT1 expression (Non-Patent Literature 11); (Non-Patent Literature 12); (Non-Patent Literature 13); (Non-Patent Literature 14); (Non-Patent Literature 15); (Non-Patent Literature 16) and efforts to develop LAT1 potent and selective inhibitors are proceeding (Non-Patent Literature 17). Thus far, four LAT proteins (i.e. LAT1-4) have been identified with LAT1 and LAT3 being the two isoforms which are most frequently overexpressed in tumor cells (Non-Patent Literature 18). LAT proteins import large neutral essential amino-acids (LNEAA) such as leucine, valine, isoleucine, phenylalanine and tyrosine in exchange with glutamine. In order to be transport functional, LAT1 requires a disulfide-linkage bound to a single membrane spanning protein 4F2 cell surface antigen heavy chain (CD98hc/4F2hc; encoded by SLC3A2 gene) (Non-Patent Literature 11); it is also known to interact with β integrins (Non-Patent Literature 19). The observed LAT1 expression at the tPTEN−/− and T-ALL/T-LL cell surface presumable equates to higher essential amino acid uptake and thereby speculated to be a contributing factor to T-ALL/T-LL leukemia cell growth and survival.
Thus, the main aim of the research by the present inventors was to perform studies to probe the potential pharmacological role(s) of targeting LAT1 by utilizing COMPOUND-JP, a potent and selective LAT1 inhibitor (Non-Patent Literature 18); (Non-Patent Literature 17); (Non-Patent Literature 20).